Fluorination process

ABSTRACT

According to the present invention there is provided a process for the selective introduction of one or more fluorine atoms into a disubstituted aromatic compound in an acid medium with fluorine gas characterized in that the acid medium has a dielectric constant of at least 20 and a pH of less than 3. The present process provides a cost effective means of selectively introducing one or more fluorine atoms into an aromatic compound in good overall yield.

This application is 371 of PCT/GB94/02732, filed Dec. 12, 1994, which isnow published as WO95/16649 on Jun. 22, 1995.

This invention relates to a process for the fluorination of aromaticcompounds.

Processes for the fluorination of aromatic compounds are known wherefluorine gas is used as a fluorinating agent but the strong oxidisingproperties of fluorine cause the aromatic compound to decompose and pooryields of the required products are obtained. The dilution of thefluorine gas with an inert gas, such as nitrogen, is described inEP-A2-0512715 and this moderates the oxidising effect of the fluorineallowing the introduction of one fluorine atom into the aromaticcompound in good yield. Known processes for the preparation ofpolyfluoroaromatic compounds involves using more severe fluorinatingconditions with a consequent increase in the formation of decompositionproducts or involves halogen exchange or reaction of an aromaticcompound with a fluorinating agent such as cobalt trifluoride.

The direct fluorination of certain aromatic compounds in acetonitrile isknown but is generally inconvenient because low reaction temperaturesare required. Further problems occur where fluorination is carried outin solvents such as acetonitrile since reaction with the solvent leadingto tar formation can occur.

The object of the present invention is to provide a fluorination processfor making specific fluorinated compounds by the selective introductionof one or more fluorine atoms into an aromatic compound in good overallyield which may be operated at easily obtainable temperatures and whichminimises reaction between fluorine and the solvent.

According to the present invention there is provided a process for theselective introduction of one or more fluorine atoms into adisubstituted aromatic compound by reaction of the aromatic compound inan acid medium with fluorine gas characterised in that the acid mediumhas a dielectric constant of at least 20 and a pH of less than 3.

The present process provides a cost effective means of selectivelyintroducing one or more fluorine atoms into an aromatic compound in goodoverall yield.

The aromatic compound is preferably benzene which may be substituted byfrom one to five substituents. Suitable substituents may beindependently selected from alkyl, alkoxy, halogen, --CN, --OH, --NO₂,--N(alkyl)₂, --NHCOalkyl, --COOalkyl, --COOH, --COalkyl, --CON(alkyl)₂,--COY, --CY¹ ₃ and --SO₂ Y² in which Y is --H, --F, --Cl, --Br, Y¹ is--F or --Cl, and Y² is --F, --Cl, --Br, --N(alkyl)₂. In each of thesesubstituents alkyl is preferably C₁₋₄ -alkyl, alkoxy is preferably C₁₋₄-alkoxy and halogen is preferably --F, --Cl or Br.

Preferred substituents for the aromatic compound are selected from --CN,--OH, --NO₂, --NHCOCH₃, --OCH₃, --COOCH₃, --COOH, --COCH₃, --CH₃, --Cl,--Br and --F and combinations thereof. The aromatic compound ispreferably disubstituted in the 1- and 4-positions or in the 1- and2-positions and more preferably disubstituted in the 1- and 4-positions.

Where the aromatic compound is disubstituted the 1-position ispreferably occupied by a meta-directing group and the 2- or 4-positionis preferably occupied by an ortho/para-directing group.

In a preferred embodiment of the present invention the aromatic compoundis of Formula (1): ##STR1## wherein:

R¹ is a meta-directing group;

X¹, X³ and X⁵ each independently is --H, --F or an ortho/para-directinggroup;

X² and X⁴ each independently is --H, halogen;

provided that at least one of X¹, X², X³, X⁴, X⁵ is --H.

The meta-directing group represented by R¹ is preferably selected from--Br, --Cl, --F, --NO₂, --CN, --COY, --CY¹ ₃ and --SO₂ Y² in which Y is--H, --F, --Cl, --Br, --C₁₋₄ -alkyl, --OH or --OC₁₋₄ -alkyl;

Y¹ is --F or --Cl;

Y² is --F, --Cl, --Br, --NH₂, --NH(C₁₋₄ -alkyl) and --NH(C₁₋₄ -alkyl)₂.

The ortho/para-directing groups represented by X¹, X³ and X⁵ arepreferably selected from --OH, --OC₁₋₆ -alkyl, C₁₋₆ -alkyl and--NHCOC₁₋₆ -alkyl.

Where one of the groups represented by X² and X⁴ is halogen it ispreferably --F or --Cl and where any of these groups are alkyl, alkoxy,--NH(alkyl) or --N(alkyl)₂ it is preferred that each alkyl or alkoxycontains from 1 to 6 carbon atoms.

Compounds of Formula (1) are preferably those in which R¹ is ameta-directing group, one of X¹, X³ or X⁵ is an ortho/para-directinggroup or --F and X² and X⁴ are hydrogen, more preferably those in whichR¹ is a meta-directing group, X³ is an ortho/para-directing group or --Fand X¹, X², X⁴ and X⁵ are hydrogen.

Especially preferred compounds of Formula (1) are those in which R¹ isselected from --CN, --NO₂, --COOCH₃, --COOH, --COCH₃, --Br, --Cl and--F, X³ is selected from --OH, --OCH₃, --CH₃, --NHCOCH₃ and --F and X¹,X², X⁴ and X⁵ are hydrogen.

The acid medium preferably has a dielectric constant from 20 to 90, morepreferably from 30 to 90, especially from 50 to 90. The acid mediumpreferably has a pH of less than 3, more preferably less than 2 andespecially less than 1.

The acid medium is preferably selected from formic and sulphuric acidsand oleum. Where the acid medium is formic or sulphuric acid it maycontain water preferably from 5 to 0% water, more preferably from 2 to0% water and especially from 1 to 0% water. Where the acid medium isoleum it is preferably from 1% to 30% oleum more preferably from 20% to30% oleum. Inert diluents, particularly fluorinated solvents such as`ARKLONE` P (ARKLONE is a trade mark of ICI PLC) may be present in theacid medium such solvents should be substantially free from water. Theacid medium is preferably sulphuric or formic acid, more preferably from95% to 100% sulphuric acid, more preferably from 95% to 97% formic acidand especially from 96% to 97% formic acid.

The use of from 98% to 100% sulphuric or particularly from 95% to 97%formic acid as the acid medium is advantageous where multiple fluorineatoms are to be introduced into the aromatic compound because such acidsallow high conversion of the aromatic compound of Formula (1) to di-,tri-, tetra- and penta-fluorinated derivatives.

The process may be carried out at a temperature from 10° C. to 90° C.,preferably at a temperature from 10° C. to 40° C. and especially from10° C. to 20° C.

The fluorine gas is preferably diluted before use by mixing with aninert gas such as nitrogen or helium. The concentration of fluorine ininert gas is preferably from 1% to 50% by volume, more preferably from2% to 25% and especially from 5% to 15%.

The ratio of fluorine to aromatic compound may be varied within widelimits although it is preferred that the molar ratio of fluorine toaromatic compound is from 1.2:1 to 6:1, depending on the degree offluorination required. Use of the higher ratio of fluorine to aromaticcompound ensures that multiple fluorine atoms are introduced into thearomatic compound forming polyfluorinated products.

When fluorination is substantially complete the fluorinated product(s)may be isolated by purging the reaction mixture with nitrogen to removeany residual fluorine and hydrogen fluoride followed by dilution withexcess water and extraction into a suitable solvent followed bydistillation. The fluorinated products may be separated by fractionaldistillation or by crystallisation from a suitable solvent.

Under the above process conditions a mixture of products is obtainedwhere one or more fluorine atoms have been introduced into the aromaticcompound. For example when 4-fluorobenzoic acid is the aromatic compoundand 98% sulphuric acid is used as the acid medium the mixture ofproducts obtained comprises 2,4- and 3,4-difluoro-, 2,4,5-, 2,3,4- and3,4,5-trifluoro-, 2,3,4,5-tetrafluoro- and 2,3,4,5,6-pentafluorobenzoicacids.

The present process thus offers a convenient synthetic route to mono-and polyfluorinated aromatic compounds which are difficult to prepare byother processes or may only be prepared in poor yield and minimises theneed to dispose of waste fluorinated tars and other by-products. Themono- and polyfluorinated products find uses as synthetic intermediatesin the preparation of agrochemicals and pharmaceuticals.

The invention is further illustrated by the following examples.

A comparative example, Example A, is provided to illustrate the effectof replacing the acid medium by an organic solvent (acetonitrile) inwhich only one fluorine atom is introduced in relatively poor yield intothe starting material. No more highly fluorinated aromatic could beisolated from the reaction mixture.

EXAMPLE 1 Fluorination of 4-Cyanophenol

A stirred reaction vessel charged with 4-cyanophenol (11.9 g, 0.1 mol)and 96% formic acid (200 cm³) was purged with nitrogen and cooled to 10°C. Fluorine (0.2 mol), diluted with nitrogen to 10%, was passed throughthe cooled, stirred solution over a period of about 6 hours. The vesselwas purged with nitrogen and allowed to warm to ambient temperature. Thereaction mixture was poured into water and extracted with diethyl ether.The extracts were dried and the solvent was removed by distillation toleave a tan solid (12.4 g). Short path distillation of the crude product(3.9 g) at reduced pressure gave an off white solid (3.4 g) which wasshown to comprise three main compounds by nmr and GC analysis. Themixture was shown to contain 4-cyano-2-fluorophenol (δ_(F) -134.7 ppm d₆-Me₂ CO!) and 4-cyano-2,6-difluorophenol (δ_(F) -131.0 ppm d₆ -Me₂ CO!)in yields of 64% and 10%, respectively, with a conversion of 84%. (NBThe chemical shifts in this and all other examples were relative toCFCl₃.)

EXAMPLE 2 Fluorination of 4-Nitrophenol

In a similar manner to that described in Example 1, 0.2 mol fluorinediluted with nitrogen to 10% was passed through a solution of4-nitrophenol (0.1 mol) in 96% formic acid over 4.5 hours at 10° C. Thereaction mixture was poured into water and extracted with diethylether.The ether solution was dried and the solvent removed using a rotaryevaporator to leave a brown liquid. This was transferred to a short pathdistillation apparatus and distilled at reduced pressure to yield paleyellow crystals (12.9 g). GC/MS and ¹⁹ Fnmr (CDCl₃) analysis showedthese to be mainly unreacted starting material, 2-fluoro-4-nitrophenol(M⁺ 157, δ_(F) -137.5 ppm, yield 70%), and 2,6-difluoro-nitrophenol (M⁺175, δ_(F) -131.7 ppm, yield 7%). The conversion was 75%.

EXAMPLE 3 Fluorination of 4-Nitroacetanilide

By the method outlined in Example 1, 4-nitroacetanilide was fluorinatedto give 2-fluoro-4-nitroacetanilide (M⁺ 198, δ_(F) -125.8 ppm CDCl₃ !,yield 60%) and 2,6-difluoro-4-nitroacetanilide (δ_(F) -112.8 ppm CDCl₃!, yield 8%). Conversion 100%.

EXAMPLE 4 Fluorination of Methyl 4-methoxybenzoate

By the method outlined in Example 1, methyl 4-methoxybenzoate wasfluorinated to give methyl 3-fluoro-4-methoxybenzoate (M⁺ 184, δ_(F)-135.3 ppm CDCl₃ !, yield 50%) and methyl 3,5-difluoro-4-methoxybenzoate(M⁺ 202, δ_(F) -128.3 ppm CDCl₃ !, yield 10%). Conversion 90%.

EXAMPLE 5 Fluorination of 4-Methoxybenzonitrile

By the method outlined in Example 1, 4-methoxybenzonitrile wasfluorinated to give 3-fluoro-4-methoxybenzonitrile (δ_(F) -125.8 ppmCDCl₃ !, yield 35%) and 3,5-difluoro-4-methoxybenzonitrile (δ_(F) -132.5ppm CDCl₃ !, yield 10%). Conversion 90%.

EXAMPLE 6 Fluorination of 4-Hydroxyacetophenone

By the method outlined in Example 1, 4-hydroxyacetophenone wasfluorinated to give 3-fluoro-4-hydroxyacetophenone (δ_(F) -133.1 ppm d₆-Me₂ CO!, yield 40%) and 3,5-difluoro-4-hydroxyacetophenone (δ_(F)-132.9 ppm d₆ -Me₂ CO!, yield 7%). Conversion 83%

EXAMPLE 7 Fluorination of Methyl 4-hydroxybenzoate

By the method outlined in Example 1, methyl 4-hydroxybenzoate wasfluorinated to give methyl 3-fluoro-4-hydroxybenzoate (δ_(F) -133.2 ppmd₆ -Me₂ CO!, yield 30%) and methyl 3,5-difluoro-4-hydroxybenzoate (δ_(F)-129.1 ppm d₆ -Me₂ CO!, yield 17%). Conversion 100%.

EXAMPLE 8 Fluorination of 4--Nitrotoluene

By the method outlined in Example 1, 4-nitrotoluene was fluorinated togive 2-fluoro-4-nitrotoluene (M⁺ 155, δ_(F) -113.4 ppm CDCl₃ !, yield50%) and a trace of 2,6-difluoro-4-nitrotoluene (M⁺ 173, δ_(F) -110.2ppm CDCl₃ !). Conversion 63%.

EXAMPLE 9 Fluorination of 4-Nitroanisole

By the method outlined in Example 1, 4-nitroanisole was fluorinated togive 2-fluoro-4-nitroanisole (M⁺ 171, δ_(F) -131.6 ppm CDCl₃ !, yield50%) and 2,6-difluoro-4-nitroanisole (M⁺ 189, δ_(F) -125.1 ppm CDCl₃ !,yield 20%). Conversion 60%.

EXAMPLE 10 Fluorination of 4-cyanotoluene

By the method outlined in Example 1, p-tolunitrile was fluorinated togive 4-cyano-2-fluorotoluene (M⁺ 135, δ_(F) -114.5 ppm CDCl₃ !, yield60%) and 4-cyano-2,6-difluorotoluene (M⁺ 153, δ_(F) -111.1 ppm CDCl₃ !,yield 2%). Conversion 86%.

EXAMPLE 11 Fluorination of 4-Chloroanisole

By the method outlined in Example 1, 4-chloroanisole was fluorinated togive 4-chloro-2-fluoroanisole (M⁺ 160, δ_(F) -132.7 ppm CDCl₃ !, yield50%) and 4-chloro-2,6-difluoroanisole (M⁺ 178, δ_(F) -127.1 ppm CDCl₃ !,yield 7%). Conversion 80%.

Fluorinations of 4-Fluorobenzoic acid

In each of the following examples the mixtures of fluoro andpolyfluorobenzoic acids were analysed first, by comparison of the 19_(F)nmr spectra of the mixtures, with the spectra of authentic samples. Moreaccurate quantitative analysis of the components in these mixtures wasobtained by conversion of the carboxylic acids to their more volatilesilyl esters, by treatment with bis(trimethylsilyl)acetamide (BSA) andthen analysis of g.c./mass spec. Therefore the quoted mass-spectrometrydata refers to the corresponding silyl esters.

EXAMPLE 12 Formic acid (substrate to fluorine ratio 1:1.6)

A solution containing 4-fluorobenzoic acid (11.5 g, 82.1 mmol) in 96%formic acid (200 cm³) was placed in a fluorination apparatus withattached soda lime filled drying tube. Fluorine gas (133 mmol) as a 10%mixture in nitrogen was then passed through the stirred solution usingnarrow bore PTFE tubing at ca 60 cm³ /min⁻¹. The mixture was added to anexcess of water (1000 cm³) and the resulting solid product was filteredoff under vacuum. The filtrate was then extracted with dichloromethane(3×50 cm³). After drying (MgSO₄), the dichloromethane was removed undervacuum and an off-white solid resulted (10.5 g).

Analysis of the resulting solid by ¹⁹ Fnmr against an external standardof fluorobenzene (7.3 g, 50.1 mmol) showed a conversion of 32% from4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid (7.8g), δF -104.2, electron impact, m/z 212 (M⁺, 3.2%), 197 (--CH₃, 100%);3,4-difluorobenzoic acid (2.7 g), δF -128.7 and -136.5, electron impact,m/z 230 (M⁺, 2.4%), 215 (--CH₃, 100%) and unidentified material (0.1 g).

EXAMPLE 13 Formic acid (substrate to fluorine ratio 1:2)

A solution containing 4-fluorobenzoic acid (11.5 g, 82.1 mmol) in 96%formic acid (200 cm³) was placed in a fluorination apparatus withattached soda lime filled drying tube. Fluorine gas (165 mmol) as a 10%mixture in nitrogen was then passed through the stirred solution usingnarrow bore PTFE tubing at ca 60 cm³ /min⁻¹. The mixture was added to anexcess of water (1000 cm³) and the resulting solid product was filteredoff under vacuum. The filtrate was then extracted with dichloromethane(3×50 cm³). After drying (MgSO₄), the dichloromethane was removed undervacuum and an off-white solid resulted (8.8 g).

Analysis of the resulting solid by ¹⁹ Fnmr against an external standardof fluorobenzene (10.2 g, 69.9 mmol) showed a conversion of 51.5% from4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid (5.6g), δF -104.2, electron impact₉ m/z 212 (M⁺, 3.24%), 197 (--CH₃, 100%);3,4-difluorobenzoic acid (2.8 g,), δF -128.7 and -136.5, electronimpact, m/z 230 (M⁺, 2.40%) , 215 (--CH₃, 100%) and unidentifiedmaterial (0.4 g).

EXAMPLE 14 Formic acid (substrate to fluorine ratio 1:3)

A solution containing 4-fluorobenzoic acid (4.0 g, 28.2 mmol) in 96%formic acid (200 cm³) was placed in a fluorination apparatus withattached soda lime filled drying tube. Fluorine gas (82.5 mmol) as a 10%mixture in nitrogen was then passed through the stirred solution usingnarrow bore PTFE tubing at ca 60 cm³ /min⁻¹. The mixture was added to anexcess of water (1000 cm³) and the resulting solid product was filteredoff under vacuum. The filtrate was then extracted with dichloromethane(3×50 cm³). After drying (MgSO₄), the dichloromethane was removed undervacuum and an off-white solid resulted (3.1 g).

Analysis of the resulting solid by ¹⁹ Fnmr against an external standardof trifluorotoluene (1.7 g, 11.6 mmol) showed a conversion of 65.3% from4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid (1.4g), δF -104.2, electron impact, m/z 212 (M⁺, 3.2%), 197 (--CH₃, 100%);3,4-difluorobenzoic acid (1.6 g,), δF -128.7 and -136.5, electronimpact, m/z 230 (M⁺, 2.4%), 215 (--CH₃, 100%) and unidentified material(0.2 g).

EXAMPLE 15 Formic acid (substrate to fluorine ratio 1:4)

A solution containing 4-fluorobenzoic acid (6.0 g, 42.9 mmol) in 96%formic acid (200 cm³) was placed in a fluorination apparatus withattached soda lime filled drying tube. Fluorine gas (165 mmol) as a 10%mixture in nitrogen was then passed through the stirred solution usingnarrow bore PTFE tubing at ca 60 cm³ /min⁻¹. The mixture was added to anexcess of water (1000 cm³) and the resulting solid product was filteredoff under vacuum. The filtrate was then extracted with dichloromethane(3×50 cm³). After drying (MgSO₄), the dichloromethane was removed undervacuum and a white solid resulted (5.3 g).

Analysis of the resulting solid by ¹⁹ Fnmr against an external standardof trifluorotoluene (5.7 g, 38.9 mmol) showed a conversion of 79.2% from4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid (1.2g), δF -104.2, electron impact, m/z 212 (M⁺, 3.2%), 197 (--CH₃, 100%);3,4-difluorobenzoic acid (3.5 g), δF -128.7 and -136.5, electron impact,m/z 230 (M⁺, 2.4%), 215 (--CH₃, 100%); 2,4,5-trifluorobenzoic acid (0.2g), δF -108.2, -123.4 and -141.3, electron impact, m/z 248 (M⁺, 1.2%),233 (--CH₃, 100%); 2,3,4-trifluorobenzoic acid (0.1 g), δF -124.4,-128.7 and -158.7, electron impact, m/z 233 (--CH₃, 5.1%);3,4,5-trifluorobenzoic acid (0.2 g), δF -132.6 and -151.3, electronimpact, m/z 248 (M⁺, 1.5%), 233 (--CH₃, 94.6%) and unidentified material(0.3 g).

EXAMPLE 16 Sulphuric acid (98%) (substrate to fluorine ratio 1:1.6)

A solution containing 4-fluorobenzoic acid (14.4, 102.9 mmol) in 98%sulphuric acid (150 cm³) was placed in a fluorination apparatus withattached soda lime filled drying tube. Elemental fluorine (165 mmol) asa 10% mixture in nitrogen was then passed through the stirred solutionusing narrow bore PTFE tubing at ca 60 cm³ /min⁻¹. The resulting mixturewas worked up by adding the mixture to an excess of water (1000 cm³) andthe resulting solid product was filtered off under vacuum. The filtratewas then extracted with dichloromethane (3×50 cm³). After drying(MgSO₄), the dichloromethane was removed under vacuum and a white solidresulted (11.6 g).

Analysis of the resulting solid by ¹⁹ Fnmr against an external standardof trifluorotoluene (mmol) showed a conversion of 82.6% from4-fluorobenzoic acid. The product containing 4-fluorobenzoic acid (2.5g), δF -104.2, electron impact, m/z 212 (M⁺, 3.28%), 197 (--CH₃, 100%);3,4-difluorobenzoic acid (6.8 g), δF -128.7 and -136.5, electron impact,m/z 230 (M⁺, 2.76%), 215 (--CH₃, 100%); 2,4,5-trifluorobenzoic acid (1.3g), δF -108.2, -123.3 and -141.2, electron impact, m/z 248 (M⁺, 1.09%),233 (--CH₃, 100%); 2,3,4-trifluorobenzoic (0.6 g), δF -124.3, -128.7 and-158.6, electron impact, m/z 248 (M⁺, 2.29%), 233 (--Cl₃, 93.90%);3,4,5-trifluorobenzoic acid (0.3 g), δF -132.6 and -151.2, electronimpact, m/z 248 (M⁺, 1.31%), 233 (--CH₃, 100%) and unidentified material(0.2 g).

EXAMPLE 17 Sulphuric acid (98%) (substrate to fluorine ratio 1:2)

A solution containing 4-fluorobenzoic acid (11.5 g, 82.5 mmol) in 98%sulphuric acid (150 cm³) was placed in a fluorination apparatus withattached soda lime filled drying tube. Elemental fluorine (165 mmol) asa 10% mixture in nitrogen was then passed through the stirred solutionusing narrow bore PTFE tubing at ca 60 cm³ /min⁻¹. The resulting mixturewas worked up by adding the mixture to an excess of water (1000 cm³) andthe resulting solid product was filtered off under vacuum. The filtratewas then extracted with dichloromethane (3×50 cm³). After drying(MgSO₄), the dichloromethane was removed under vacuum and a white solidresulted (10.6 g).

Analysis of the resulting solid by ¹⁹ Fnmr against an external standardof trifluorotoluene (3.2 g, 21.8 mmol) showed a conversion of 34.8% from4-fluorobenzoic acid. The product containing 4-fluorobenzoic acid (1.8g), δF -104.2, electron impact, m/z 212 (M⁺, 3.3%), 197 (--CH₃, 100%);3,4-difluorobenzoic acid (6.2 g), δF -128.7 and -136.5, electron impact,m/z 230 (M⁺, 2.8%), 215 (--CH₃, 100%); 2,4,5-trifluorobenzoic acid (0.3g), δF -108.2, -123.3 and -141.2, electron impact, m/z 248 (M⁺, 1.1%),233 (--CH₃, 100%); 2,3,4-trifluorobenzoic (0.4 g), δF -124.3, -128.7 and-158.6, electron impact, m/z 248 (M⁺, 2.3%), 233 (--CH₃, 93.9%);3,4,5-trifluorobenzoic (0.4 g), 8F-132.6 and -151.2, electron impact,m/z 248 (M⁺, 1.3%), 233 (--CH₃, 100%); 2,3,4,5-tetrafluorobenzoic acid(0.7 g), SF-133.3, -137.9, -142.7 and -151.2, electron impact, m/z 266(M⁺, 0.5%), 251 (--CH₃, 60.3%) and unidentified material (0.4 g).

EXAMPLE 18 Sulphuric acid (98%) (substrate to fluorine ratio 1:3)

A solution containing 4-fluorobenzoic acid (7.7 g, 55.0 mmol) in 98%sulphuric acid (150 cm³) was placed in a fluorination apparatus withattached soda lime filled drying tube. Elemental fluorine (165 mmol) asa 10% mixture in nitrogen was then passed through the stirred solutionusing narrow bore PTFE tubing at ca 60 cm³ /min⁻¹. The resulting mixturewas worked up by adding the mixture to an excess of water (1000 cm³) andthe resulting solid product was filtered off under vacuum. The filtratewas then extracted with dichloromethane (3×50 cm³). After drying(MgSO₄), the dichloromethane was removed under vacuum and a white solidresulted (5.9 g).

Analysis of the resulting solid by ¹⁹ Fnmr against an external standardof trifluorotoluene (3.6 g, 24.9 mmol) showed a conversion of 92.3% from4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid (0.6g), δF -104.2, electron impact, m/z 212 (M⁺, 3.28%), 197 (--CH₃, 100%);3,4-difluorobenzoic acid (3.4 g), δF -128.7 and -136.5, electron impact,m/z 230 (M⁺, 2.8%), 215 (--CH₃, 100%); 2,4,5-trifluorobenzoic acid (0.6g), δF -108.2, -123.3 and -141.2, electron impact, m/z 248 (M⁺, 1.1%),233 (--CH₃, 100%); 2,3,4-trifluorobenzoic acid (0.2 g), δF -124.3,-128.7 and -158.6, electron impact, m/z 248 (M⁺, 2.3%), 233 (--CH₃,93.9%); 3,4,5-trifluorobenzoic acid (0.5 g), δF -132.6 and -151.2,electron impact m/z 248 (M⁺, 1.3%), 233 (--CH₃, 100%);2,3,4,5-tetrafluorobenzoic acid (0.3 g), δF -133.3, -137.9, -142.7 and-151.2, electron impact, m/z 266 (M⁺, 0.5%), 251 (--CH₃, 60.3%) andunidentified material (0.3 g).

Comparative Example A Fluorination of 4-Fluorobenzoic Acid inAcetonitrile

A solution containing 4-fluorobenzoic acid (1.6 g, 11.3 mmol) inacetonitrile (80 cm³) was placed in a fluorination apparatus fitted witha tube filled with soda lime. Fluorine gas (35 mmol) as a 10% mixture innitrogen was then passed through the stirred solution at 25° C. usingnarrow bore PTFE tubing at ca 4.0 cm³ /min⁻¹. The mixture was added toan excess of water (500 cm³) followed by extraction with dichloromethane(3×25 cm³). After drying (MgSO₄), dichloromethane was removed undervacuum leaving brown solid (1.6 g).

Analysis of the solid by ¹⁹ Fnmr after preparing the silyl esterderivatives by reacting the product with bis trimethylsilyl acetamideagainst an external standard of fluorobenzene (0.2 g, 3.9 mmol) showed aconversion of 85% from 4-fluorobenzoic acid. The product contained4-fluorobenzoic acid, δF -104.4, electron impact, m/z 212 (M⁺, 3.5%),197 (--CH₃, 100%) and 3,4-difluorobenzoic acid, 66%, δF -128.8 and-136.7, electron impact, m/z 230 (M⁺, 2.6%), 215 (--CH₃, 100%) in aratio of 33% to 66% and unidentified material.

EXAMPLE 19 Fluorination of 4-Fluorobenzoic Acid in Formic Acid

A solution containing 4-fluorobenzoic acid (1.6 g, 11.3 mmol) in 98%formic acid (80 cm³) was placed in a fluorination apparatus fitted witha tube filled with soda lime. Fluorine gas (35 mmol) as a 10% mixture innitrogen was then passed through the stirred solution at 25° C. usingnarrow bore PTFE tubing at ca 4.0 cm³ /min⁻¹. The mixture was added toan excess of water (500 cm³) followed by extraction with dichloromethane(3×25 cm³). After drying (MgSO₄), dichloromethane was removed undervacuum leaving an off-white solid (0.7 g).

Analysis of the solid by ¹⁹ Fnmr after preparing the silyl esterderivatives by reacting the product with bis trimethylsilyl acetamideagainst an external standard of fluorobenzene (0.2 g, 3.9 mmol) showed aconversion of 98% from 4-fluorobenzoic acid. The product contained4-fluorobenzoic acid, 8F -104.2, electron impact, m/z 212 (M⁺, 3.2%),197 (--CH₃, 100%); 3,4-difluorobenzoic acid, δF -128.7 and -135.5,electron impact, m/z 230 (M⁺, 2.4%), 215 (--CH₃, 100%);2,4,5-trifluorobenzoic acid, δF -108.2, 123.4 and -141.3, electronimpact, m/z 248 (M⁺, 1.2%), 233 (--CH₃, 100%); 2,3,4-trifluorobenzoic,δF -124.4, -128.7 and -158.7, electron impact, m/z 233 (--CH₃, 5.1%) and3,4,5-trifluorobenzoic acid, δF -132.6 and -151.3, electron impact, m/z248 (M⁺, 1.5%), 233 (--CH₃, 94.6%) in a ratio of 8%:73%:8%:4%:7% andunidentified material.

EXAMPLE 20 Fluorination of 4-Fluorobenzoic Acid in Sulphuric Acid (98%)

A solution containing 4-fluorobenzoic acid (1.6 g, 11.3 mmol) in 98%sulphuric acid (80 cm³) was placed in a fluorination apparatus fittedwith a tube filled with soda lime. Fluorine gas (35 mmol) as a 10%mixture in nitrogen was then passed through the stirred solution at 25°C. using narrow bore PTFE tubing at ca 4.0 cm³ /min⁻¹. The mixture wasadded to an excess of water (500 cm³) followed by extraction withdichloromethane (3×25 cm³). After drying (MgSO₄), dichloromethane wasremoved under vacuum leaving an off-white solid (1.3 g).

Analysis of the solid by ¹⁹ Fnmr after preparing the silyl esterderivatives by reacting the product with bis trimethylsilyl acetamideagainst an external standard of fluorobenzene (0.2 g, 2.3 mmol) showed aconversion of 97% from 4-fluorobenzoic acid. The product contained4-fluorobenzoic acid, δF -104.2, electron impact, m/z 212 (M⁺, 3.3%),197 (--CH₃, 100%); 2,4-difluorobenzoic acid, δF -97.6, -100.0;3,4-difluorobenzoic acid, δF -128.7 and -136.5, electron impact, m/z 230(M⁺, 2.8%), 215 (--CH₃, 100%) ; 2,4,5-trifluorobenzoic acid, δF -108.2,-123.3 and -141.2, electron impact, m/z 248 (M⁺, 1.1%), 233 (--CH₃,100%); 2,3,4-trifluorobenzoic, δF -124.3, -128.7 and -158.6, electronimpact, m/z 248 (--CH₃, 2.3%); 3,4,5-trifluorobenzoic acid, δF -132.6and -151.2, electron impact, m/z 248 (M⁺, 1.3%), 233 (--CH₃, 100%);2,3,4,5-tetrafluorobenzoic acid, δF -133.3, -137.9, -142.7 and -151.2,electron impact, m/z 266 (M⁺, 0.5%), 251 (--CH₃, 60.3%);2,3,4,5,6-pentafluorobenzoic acid, δF -136.9, -146.8 and -158.6,electron impact, m/z 269 (--CH₃, 0.9%) in a ratio of6%:2%:61%:9%:6%:9%:6%:1%and unidentified material.

EXAMPLE 21 Fluorination of 4-Fluorobenzoic Acid in Oleum (30%. SO₃)

A solution containing 4-fluorobenzoic acid (1.6 g, 11.3 mmol) in 30%oleum (80 cm³) was placed in a fluorination apparatus fitted with a tubefilled with soda lime. Fluorine gas (35 mmol) as a 10% mixture innitrogen was then passed through the stirred solution at 25° C. usingnarrow bore PTFE tubing at ca 4.0 cm³ /min⁻¹. The mixture was added toan excess of water (500 cm³) followed by extraction with dichloromethane(3×25 cm³). After drying (MgSO₄), dichloromethane was removed undervacuum leaving a white solid (1.3 g).

Analysis of the solid by ¹⁹ Fnmr after preparing the silyl esterderivatives by reacting the product with bis trimethylsilyl acetamideagainst an external standard of fluorobenzene (0.4 g, 4.6 mmol) showed aconversion of 88% from 4-fluorobenzoic acid. The product contained4-fluorobenzoic acid, δF -104.3, electron impact, m/z 212 (M⁺, 3.4%),197 (--CH₃, 100%); 3,4-difluorobenzoic acid, δF -128.9 and -136.5,electron impact, m/z 230 (M⁺, 2.6%), 215 (--CH₃, 100%);2,4,5-trifluorobenzoic acid, δF -108.2, -123.3 and -141.2, electronimpact, m/z 248 (M⁺, 1.3%), 233 (--CH₃, 100%); 2,3,4-trifluorobenzoic,δF -124.3, -128.7 and -158.6, electron impact, m/z 248 (--CH₃, 2.5%),233 (--CH₃, 93.2%); 3,4,5-trifluorobenzoic acid, δF -132.7 and -151.5,electron impact, m/z 248 (M⁺, 1.2%), 233 (--CH₃, 94.3%);2,3,4,5-tetrafluorobenzoic acid, δF -133.3, -137.9, -142.7 and -151.2,electron impart, m/z 251 (--CH₃, 60.3%); 2,3,4,5,6-pentafluorobenzoicacid, δF -136.9, -146.8 and -158.6 in a ratio of24%:55%:5%:4%:8%:3%:1%and unidentified material.

We claim:
 1. A process for the selective introduction of one or morefluorine atoms into an aromatic compound substituted with at least twosubstituents which are not hydrogen and having at least one positionsubstituted only with hydrogen by reaction of the aromatic compound withfluorine gas in an acid medium having a dielectric constant of at least20, a pH of less than 3 and containing less than 5% water, whereby saidat least one position substituted only with hydrogen is replaced byfluorine.
 2. A process according to claim 1 in which the acid medium isselected from formic and sulphuric acids and oleum.
 3. A processaccording to claim 1 in which the fluorine gas is diluted with an inertgas.
 4. A process according to claim 2 in which the acid medium issulphuric or formic acid.
 5. A process according to claim 2 in which thefluorine gas is diluted with an inert gas.
 6. A process according toclaim 4 in which the fluorine gas is diluted with an inert gas.
 7. Aprocess according to claim 4 wherein the acid medium contains at least95% sulphuric acid or at least 95% formic acid.
 8. A process accordingto claim 7 wherein the acid medium contains at least 96% sulphuric acidor at least 98% formic acid.
 9. A process according to claim 1 whereinthe substituents, which may be the same or different, are selected fromthe group consisting of alkyl, alkoxy, halogen, --CN, --OH, --NO₂,--N(alkyl)₂, --NHCOalkyl, --COO(alkyl), --COOH, --CO(alkyl),--CON(alkyl)₂, --COY, --CY¹ ₃ and --SO₂ Y², wherein Y is --H, --F, --Cl,or --Br, Y¹ is --F or --Cl, and Y² is --F, --Cl, --Br, or --N(alkyl)₂.10. A process according to claim 9 wherein the substituents are selectedfrom the group consisting of --CN, --OH, --No₂, --NHCOCH₃, --OCH₃,--COOCH₃, --COOH, --COCH₃, --CH₃, --Cl, --Br and --F.
 11. A processaccording to claim 1 wherein the aromatic compound is substituted in the1-position with a meta-directing group and in the 2-position or4-position with an ortho/para-directing group.
 12. A process accordingto claim 1 wherein the aromatic compound is benzene.
 13. A processaccording to claim 12 wherein the benzene is substituted with 2-5substituents.
 14. A process according to claim 13 wherein thesubstituents, which may be the same or different, are selected from thegroup consisting of alkyl, alkoxy, halogen, --CN, --OH, --NO₂,--N(alkyl)₂, --NHCOalkyl, --COO(alkyl), --COOH, --CO(alkyl),--CON(alkyl)₂, --COY, --CY¹ ₃ and --SO₂ Y², wherein Y is --H, --F, --Cl,or --Br, Y¹ is --F or --Cl, and Y² is --F, --Cl, --Br, or --N(alkyl)₂.15. A process according to claim 14 wherein the substituents areselected from the group consisting of --CN, --OH, --NO₂, --NHCOCH₃,--OCH₃, --COOCH₃, --COOH, --COCH₃, --CH₃, --Cl, --Br and --F.
 16. Aprocess according to claim 13 wherein the benzene has the followingformula: ##STR2## wherein: R¹ is a meta-directing group;X¹, X³ and X⁵each independently is --H, --F or an ortho/para-directing group; and X²and X⁴ each independently is --H or halogen; provided that at least oneof X¹, X², X³, X⁴, X⁵ is --H.
 17. A process according to claim 16wherein R¹ is --Br, --Cl, --F, --NO₂, --CN, --COY, --CY¹ ₃ or --SO₂ Y²,wherein Y is --H, --F, --Cl, --Br, --C₁₋₄ -alkyl, --OH or --OC₁₋₄-alkyl, Y¹ is --F or --Cl, and Y² is --F, --Cl, --Br, --NH₂, --NH(C₁₋₄-alkyl) or --NH(C₁₋₄ -alkyl)₂.
 18. A process according to claim 16wherein X¹, X³ and X⁵ each is independently --OH, --OC₁₋₆ -alkyl, C₁₋₆-alkyl or --NHCOC₁₋₆ -alkyl.
 19. A process according to claim 16 whereinR¹ is --CN, --NO₂, --COOCH₃, --COOH, --COCH₃, --Br, --Cl or --F, X³ is--OH, --OCH₃, --CH₃, --NHCOCH₃ or --F, and X¹, X², X⁴ and X⁵ each ishydrogen.
 20. A process for the introduction of fluorine into the3-position of an aromatic compound substituted with a meta-directinggroup at the 1-position and an ortho/para-directing group at the4-position and having a hydrogen atom at the 3-position by reaction ofthe aromatic compound with fluorine gas in an acid medium having adielectric constant of at least 20, a pH of less than 3 and containingless than 5% water, whereby the hydrogen atom at the 3-position isreplaced by fluorine.